The present proposal is undertaken to delineate the cellular mechanism causing myocardial dysfunction following endotoxic shock in diabetics in hopes to clarify the role of the heart in pathogenesis of shock, particularly during the irreversible stage. The proposed experiments involve the following aspects: Identification of metabolic alterations in the uptake and utilization of free fatty acid, glucose, and lactate by myocytes isolated from adult dogs after endotoxic shock in non-diabetic and diabetic animals, and elucidation of the mechanisms causing these alterations; identification of rate-controlling reactions and regulatory enzymes in the glycolytic and TCA cycle pathways; elucidation of the mechanism regulating long-chain fatty acid oxidation and esterification. The information to be obtained from these studies will be useful in understanding the basic mechanism responsible for dysfunction of heart following the systemic insults mentioned above. Once the metabolic alterations are clarified and the controlling mechanisms are elucidated we will attempt to reverse the changes produced by shock and thus convert the irreversible shock to a reversible condition, particularly when the individuals are predisposed to diabetes.